Highly active antiretroviral therapy (HAART) has been successfully utilized in HIV-infected individuals to significantly reduce disease progression and improve the prognosis of infected individuals. However, the side-effects, toxicity, and drug-drug interactions of HAART therapies have resulted in reduced patient adherence to the drug regimens, fueling the development of drug resistance. Thus, a continuing need for new and improved antiretroviral agents exists. Current ARVs target five steps in HIV replication, and include inhibition of virus entry (CCR5 antagonism and fusion inhibition) and inhibition of the virus-specific enzymes reverse transcriptase, integrase and protease. Although improvements in the efficacy and toxicity of new generation inhibitors in these existing classes of drugs continues to occur, it is also important to consider the development of new and novel drugs targeting additional required steps in HIV replication. These new agents would be expected to remain fully active against existing drugresistant and multi-drug resistant viruses and thus might be highly effective supplements to existing HAART regimens or constituents of salvage therapy regimens in patients failing long courses of RT and protease inhibitor therapies. It is clear that the continued development of new agents with enhanced potency, reduced toxicity, and a greater genetic barrier to resistance, as well as targeting other HIV replication steps, is a critical need for the continued effectiveness of HIV therapy ImQuest Pharmaceuticals is developing IQP-0410, a highly potent nonnucleoside pyrimidinedione (PYD) inhibitor of HIV-1 with a molecular weight of 352 g/mole. The compound exhibited a therapeutic index of approximately one to four million in replicate antiviral assays, indicating that it was several orders of magnitude more active against HIV-1 than nevirapine and the early NNRTIs and of similar potency to Sustiva. but without the significant toxicities reported for Sustiva.. Although the primary mechanism of action of IQP-0410 is inhibition of the viral reverse transcriptase (RT), acting as a typical third generation nonnucleoside RT inhibitor (NNRTI) at sub-nanomolar concentrations, this compound also inhibits viral entry at nanomolar concentrations. The dual mechanism of action confers a high genetic barrier to the selection of IQP-0410-resistant viruses and in vitro assays have shown significant activity of IQP-0410 against clinically relevant drug resistant virus strains and against multi-drug resistant virus strains with resistance to protease inhibitors. Due to low solubility and poor penetration through the mucosa to the target site of action, pyrimidinediones face significant obstacles as a therapeutic. Therefore, strategic drug delivery designs are essential for pyrimidinediones to advance as viable HAART products. Through conventional administration, such as injections or oral, PYD would be subjected to extensive first pass metabolism by the liver limiting its effectiveness. We propose transdermal films an innovative drug delivery strategy to enhance PYD therapeutic efficacy and delivery through polymeric formulations. Specifically, transdermal films delivery has many advantages over conventional administration such as improved patient compliance in long-term therapy, bypassing first-pass metabolism, sustained drug delivery, avoiding drug peak and valley dosing in plasma, minimizing inter- and intra- patient variability, and allowing treatment termination. We propose that this project will identify a transdermal film formulation that will enhance efficacy and allow long term therapeutic delivery of IQP-0410. PUBLIC HEALTH RELEVANCE: ImQuest Pharmaceuticals is developing IQP-0410, a highly potent nonnucleoside pyrimidinedione inhibitor of HIV-1, as a therapeutic drug. ImQuest Biosciences will utilize their expertise in HIV drug development and formulation to develop a novel delivery system transdermal films. This delivery vehicle will provide constant HIV therapeutics in a solid dosage form that has the advantage of improved patient compliance in long-term therapy, bypassing first-pass metabolism, sustained drug delivery, avoiding drug peak and valley dosing in plasma, minimizing inter- and intra- patient variability, and allowing treatment termination. The research to be performed will include development of the transdermal film and the evaluation of its ability to deliver a therapeutic amount of IQP-0410 over long periods of time.